The Current and Evolving Landscape of Immunotherapies
for Advanced Renal Cell Carcinoma
Abstract
There has been tremendous progress in the treatment
landscape of metastatic renal cell carcinoma over the last
decade with new, more efficacious strategies emerging
and the incorporation of several of these therapies into
combinations with even greater benefit to patients.
Novel immune checkpoint inhibitors (ICI) have emerged
as a primary backbone to many of the most active regimens.
However, drawbacks of ICI remain such as lower
long-term response rates and the absence of potential
biomarkers that will facilitate patient selection. In addition,
current data regarding the outcomes of patients including
optimal management of patients who progress
after ICI are fairly limited. Owing to such limitations,
there is an urgent need to identify more reliable biomarkers
of immunotherapies for better prediction of treatment
response and more efficient stratification of
patients. In this review, we provide the current status of
the immunotherapy landscape for advanced renal cell
carcinoma as well as discuss future directions.
Introduction
Renal cell carcinoma (RCC) is one of the top ten most
frequently diagnosed cancers with an incidence of
around 400,000 cases worldwide.1 In United States alone,
RCC accounts for 73,820 new cases and 14,770 deaths
in 2019. In patients with RCC, about 30% of patients
who present with metastatic disease at the time of initial
diagnosis typically require systemic therapy and almost
30% of patients who are treated for localized RCC develop
recurrent disease during the follow-up.2 RCC is
typically known for its resistance to conventional forms
of therapies as hormonal and cytotoxic chemotherapeutics
have considerably failed to produce remissions and
improve overall survival. For the past several years, ongoing
clinical trial efforts were aimed at developing targeted
50 Kidney Cancer Journal
therapeutic agents for the management and treatment
of metastatic renal cell cancer (mRCC). Until 2005,
medical therapies for mRCC were limited to interferon
alpha or interleukin 2 as cytokine-based therapies
which provided only a modest survival benefit of approximately
1 year.3,4 Based on the preliminary data indicating
15% overall response rate (ORR) and a 5%
complete response (CR), the high-dose intravenous IL-2
was approved by the US Food and Drug Administration
(FDA) for the treatment of RCC in 1992. High-dose IL-2
used in selective patients with metastatic renal cell carcinoma
had led to rare complete and durable responses.3
In a follow-up study, CR was 7% and median duration
of response was at least 80 months. The scope of IL-2
based therapy is, however, limited by substantial incidence
of high-grade adverse events as well as the inability
to predict response.
In recent years, multiple targeted therapies predominantly
focusing on two major molecular pathways,
namely angiogenesis and intracellular signal transduction
pathways, have gained increasing attention in RCC
landscape. Since 2005, there has been remarkable
progress in the treatment of RCC with VEGF inhibitors
(sunitinib, sorafenib, axitinib, pazopanib, cabozantinib,
bevacizumab, lenvatinib), as well as mammalian target
of rapamycin (mTOR) pathway inhibitors (everolimus,
temsirolimus). These agents provided considerable survival
benefits in pivotal trials as well as gained regulatory
approval to become the defacto choice of first-line systemic
therapy.5 More recently, key insights obtained in
regard to the VHL pathway have profoundly shaped the
evolving mutational landscape of mRCC and also provided
the basis for the development of the VHL-hypoxia
pathway-based therapeutic landscape in renal cancers.6
Despite the significant progress over the past 15 years,
there is still room for improvement for targeted therapies
as current drug interventions for mRCC have yet to
demonstrate the ability to circumvent recurrence and
several therapies are accompanied by severe adverse
events.3,4 In this review, we summarize recent breakthroughs
in the immunotherapy space that remodeled
Allen Jacob, MD Jaret Shook Thomas E. Hutson,
DO, PharmD, FACP
Allen Jacob, MD1, Jaret Shook2, and Thomas E Hutson, DO, PharmD, FACP3
1Texas A&M College of Medicine, Bryan TX;
2Ohio Northern University College of Pharmacy, Ada, OH;
and Urologic Oncology Program,
3Texas Oncology, Baylor Sammons Cancer Center, Dallas, TX
Keywords: immune-checkpoint inhibitors, ICI, anti-angiogenics,
immunotherapy landscape, immune microenvironment reprogramming,
TKI, RCC.
Corresponding Author: Thomas E Hutson@usoncology.com
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